Tens of millions of hepatitis B virus (HBV) infections occur annually, leading to sequelae which claim an estimated one million lives each year. Furthermore, HBV infections may be accompanied by a second deadly hepatotropic pathogen, with delta hepatitis the clinical result. Although an effective HBV vaccine is available, it cannot be used to treat chronic HBV, a condition afflicting about 300 million people world wide and approximately one million Americans. Moreover, while interferons and other drugs have been evaluated in clinical trials, none has proven to be effective for the majority of patients. Thus, we are addressing the need for new therapeutics to treat hepatitis B and delta hepatitis. Many of our approaches, which all involve RNA biochemistry, have the potential to be adapted for the treatment of additional viral diseases. The anti-HBV RNA therapeutics we have designed act through a variety of biochemical pathways and will require new delivery systems. The therapeutic RNAs and the systems for delivering them to cells will be evaluated in parallel, with each having the potential to make a significant contribution to the development of new antiviral therapies. The main techniques to be employed are those needed for RNA synthesis and characterization, DNA-level genetic engineering, protein and antibody preparation, and cell and virus propagation in vitro. RNA Therapeutics for Control of HBV and Delta Hepatitis The Specific Aims of this Proposal Are: (i).To target HBV RNAs for turnover or inactivation by the therapeutic use of anti-HBV RNA molecules. (ii).To develop both fully synthetic and viral delivery systems for the introduction of anti-HBV RNAs into liver cells. (iii).To design a receptor-mediated uptake system specific for HBV-infected cells and thereby allow the safe use of cytotoxic RNA oligonucleotides.